Hormesis: from marginalization to mainstream: a case for hormesis as the default dose-response model in risk assessment

The paper provides an account of how the hormetic dose response has emerged in recent years as a serious dose-response model in toxicology and risk assessment after decades of extreme marginalization. In addition to providing the toxicological basis of this dose-response revival, the paper reexamines the concept of a default dose model in toxicology and risk assessment and makes the argument that the hormetic model satisfies criteria (e.g., generalizability, frequency, application to risk assessment endpoints, false positive/negative potential, requirements for hazard assessment, reliability of estimating risks, capacity for validation of risk estimates, public health implications of risk estimates) for such a default model better than its chief competitors, the threshold and linear at low dose models. The selection of the hormetic model as the default model in risk assessment for noncarcinogens and specifically for carcinogens would have a profound impact on the practice of risk assessment and its societal implications.     

Application of toxicokinetics to improve chemical risk assessment: Implications for the use of animals

While toxicokinetics has become an integral part of pharmaceutical safety assessment over the last two decades, its use in the chemical industry is relatively new. However, it is recognised as a potentially important tool in human health risk assessment and recent initiatives have advocated greater application of toxicokinetics as part of an improved assessment strategy for crop protection chemicals that could offer greater efficiency, use fewer animals and provide better data for risk assessment purposes. To explore the potential scientific and animal welfare benefits of increased use of toxicokinetic data across the chemical industry, an international workshop was held in 2008. Experts from a wide range of chemical industry sectors, including industrial chemicals, agrochemicals and consumer products, participated in the meeting as well as representatives from relevant regulatory authorities. Pharmaceutical industry experts were also invited, in order to share experiences from the extensive use of toxicokinetics in drug development. Given that increased generation of toxicokinetic data could potentially result in an increased number of animals undergoing testing, technologies and strategies to reduce and refine animal use for this purpose were also considered. This paper outlines and expands upon the key themes that emerged from the workshop.     

Derivation of endogenous equivalent values to support risk assessment and risk management decisions for an endogenous carcinogen: Ethylene oxide

An approach is presented for ethylene oxide (EO) to derive endogenous equivalent (EE) values, which are endogenous levels normally found within the body expressed in terms of exogenous exposures. EE values can be used to support risk assessment and risk management decisions for chemicals such as EO that have both endogenous and exogenous exposure pathways. EE values were derived using a meta-analysis of data from the published literature characterizing the distribution for an EO biomarker of exposure, hemoglobin N-(2-hydroxyethyl)-valine (HEV), in unexposed populations. These levels are compared to the those reported in exposed populations (smokers, workers). Correlation between the biomarker of exposure and external exposures of EO were applied to this distribution to determine corresponding EE values, which range from 0.13 to 6.9 ppb for EO in air. These values are orders of magnitude higher than risk-based concentration values derived for EO using default methods, and are provided as a pragmatic, data-driven alternative approach to managing the potential risks from exogenous exposures to EO.     

Variability in toxic response - relevance to chemical safety and risk assessment at the global level

The aim of control limits for exposure to chemicals in air, food, water, and consumer products is to protect the whole human population, including the most susceptible individuals and ‘at risk’ groups. The existence of susceptible individuals is a factor that must be taken into account when quantitative chemical risk assessments are being made, and should be covered in the risk characterization. Classically, when extrapolating data derived from animal experiments using homogeneous, healthy test species for human health risk assessment uncertainty factors are applied. For inter-species extrapolation an uncertainty factor of up to 10 is applied. While it is evident that this procedure provides reasonable protection for the great majority of the population there are outlyers who may not be protected under all conditions. Within a population, individual susceptibility is influenced by genetic and environmental factors. These have regional and national differences. Environmental factors that are important in many countries include ‘life-style’ (e.g. tobacco and alcohol consumption, diet), nutritional and health status. In the case of environmental protection similar considerations apply but the emphasis is on species rather than individuals. The International Programme on Chemical Safety, as the global programme on identifying and assessing chemical risks to human health and the environment in order to assist countries in effective management, is constantly advancing the basic science and methodology for making chemical risk assessment.     

In vivo genotoxicity of EMS: Statistical assessment of the dose response curves

EMS induced micronuclei and lacZ mutations in in vivo studies in mice with a clearly sublinear dose dependency. As reported elsewhere in this issue, NOEL dose values of between 25 mg/kg/day and 80 mg/kg/day were observed for the different endpoints and tissues analysed. Here we show that statistical assessment of the data provides solid support that the induction of mutagenic and clastogenic effects after in vivo treatment with the directly DNA damaging mutagen EMS adheres to a thresholded dose response relation. These data corroborate similar evidence obtained in in vitro studies. We conclude that cells are fully capable of repairing large amounts of DNA ethylations induced by EMS without experiencing elevated mutation frequencies. The stochastic, linear risk assessment model generally employed for DNA damaging genotoxins can therefore be refuted for EMS. While presently this conclusion cannot be generalized to other genotoxins a change of paradigm appears to be indicated at least for alkylating agents inducing a comparable type and spectrum of DNA lesions as EMS.     

Workshop report: identifying key issues underpinning the selection of linear or non-linear dose-response extrapolation for human health risk assessment of systemic toxicants

The report of an Expert Panel convened by the National Research Council (NRC) of the National Academy of Sciences (NAS), entitled Science and Decisions: Advancing Risk Assessment (National Research Council, 2009a), includes a recommendation to use, as a default approach, low-dose linear extrapolation for systemic toxicity. This recommendation represents a significant departure from long-standing risk assessment practices for non-cancer toxicity, where the most appropriate No Observed Adverse Effect Level (NOAEL) or Benchmark Dose (BMD) of the critical effect in the key study is selected, and then a "safe exposure" level is derived by applying uncertainty factors to account for dataset completeness, potential greater sensitivity of humans when compared with experimental animals, and for potential variability of sensitivity in humans. A workshop was held to "frame" issues raised by the NAS report that needed further study. Workshop objectives included the following: (1) identify the issues raised by the 2009 NRC report and discuss the extent to which existing science may (or may not) align with the NAS analyses and recommendations, and (2) identify/develop possible actions to assist in advancing deeper and broader considerations of some of the critical issues presented by the 2009 NAS Panel. Experts invited to this "Framing" Workshop encompassed a full spectrum of toxicology and risk assessment disciplines; in particular, expertise in molecular interactions and dose-response of biological systems were well represented. The recommendations developed at this Framing Workshop provide specific ideas on possible further steps to facilitate deeper and broader consideration of the issues underpinning dose-response extrapolation in the risk assessment of systemic toxicants.     

Accounting for susceptibility in risk assessment: The need for full disclosure

Many Environmental Laws create the unrealistic expectation that science can be used to determine ‘safety'. The many uncertainties surrounding environmental risks, as well as individual, group and societal differences about what is considered ‘safe', make it inevitable that policy decisions must be made. It is appropriate that such decisions be shaped by politics and social issues, as well as be informed by science and economics, but care should be taken to distinguish between policy and fact. Not much is known about the nature and magnitude of environmental susceptibilities. Credible environmental decisions require that scientists, risk assessors and decision-makers acknowledge this, and that they take care to distinguish policy calls from scientific fact.     

Lingering effect: epidemiological information useful for risk assessment

This article discusses cessation lag and effect lingering and their potential applications to dose–response analysis in risk assessment. Effect lingering can be used to analyze epidemiological data by uncovering the hidden biological implication related to disease endpoints, thereby advancing current characterization efforts and reducing risk assessment uncertainties. To illustrate the approach, as well as to better characterize the role of age of initiation and duration of smoking in carcinogenesis, we apply the concept of lingering effect to smoking and lung cancer data from the Cancer Prevention Study II.     

The changing face of nanomaterials: Risk assessment challenges along the value chain

Risk assessment (RA) of manufactured nanomaterials (MNM) is essential for regulatory purposes and risk management activities. Similar to RA of “classical” chemicals, MNM RA requires knowledge about exposure as well as of hazard potential and dose response relationships. What makes MNM RA especially challenging is the multitude of materials (which is expected to increase substantially in the future), the complexity of MNM value chains and life cycles, the accompanying possible changes in material properties over time and in contact with various environmental and organismal milieus, and the difficulties to obtain proper exposure data and to consider the proper dose metric. This article discusses these challenges and also critically overviews the current state of the art regarding MNM RA approaches.     

Human health risk assessment database, "the NHSRC toxicity value database": supporting the risk assessment process at US EPA's National Homeland Security Research Center

The toxicity value database of the United States Environmental Protection Agency's (EPA) National Homeland Security Research Center has been in development since 2004. The toxicity value database includes a compilation of agent property, toxicity, dose-response, and health effects data for 96 agents: 84 chemical and radiological agents and 12 biotoxins. The database is populated with multiple toxicity benchmark values and agent property information from secondary sources, with web links to the secondary sources, where available. A selected set of primary literature citations and associated dose-response data are also included. The toxicity value database offers a powerful means to quickly and efficiently gather pertinent toxicity and dose-response data for a number of agents that are of concern to the nation's security. This database, in conjunction with other tools, will play an important role in understanding human health risks, and will provide a means for risk assessors and managers to make quick and informed decisions on the potential health risks and determine appropriate responses (e.g., cleanup) to agent release. A final, stand alone MS ACESSS working version of the toxicity value database was completed in November, 2007.     

The use of information on susceptibility in risk assessment: state of the science and potential for improvement

The aim of this paper is to evaluate the use of information on susceptibility or variability in risk assessment. Are we using it well? Are we not using it well or not at all? And finally, what can we do to improve the use of information on variability in risk assessment? The presentation is organized using the risk assessment paradigm developed by the National Research Council in 1983 (National Research Council, 1983. Risk Assessment in the Federal Government: Managing the Process. National Academy Press, Washington, DC.) which conceptualized risk assessment as consisting of four phases: hazard identification, dose response assessment, exposure assessment, and risk characterization. Because risk assessment procedures differentiate cancer risk from risk for systemic toxicity (i.e. non-cancer), cancer and noncancer risk assessment are discussed separately.     

The evolution of skin notations for occupational risk assessment: a new NIOSH strategy

This article presents an overview of a strategy for assignment of hazard-specific skin notations (SK), developed by the National Institute for Occupational Safety and Health (NIOSH). This health hazard characterization strategy relies on multiple SKs capable of delineating systemic (SYS), direct (DIR), and immune-mediated (SEN) adverse effects caused by dermal exposures to chemicals. One advantage of the NIOSH strategy is the ability to combine SKs when it is determined that a chemical may cause multiple adverse effects following dermal contact (e.g., SK: SYS-DIR-SEN). Assignment of the SKs is based on a weight-of-evidence (WOE) approach, which refers to the critical examination of all available data from diverse lines of evidence and the derivation of a scientific interpretation based on the collective body of data including its relevance, quality, and reported results. Numeric cutoff values, based on indices of toxic potency, serve as guidelines to aid in consistently determining a chemical’s relative toxicity and hazard potential. The NIOSH strategy documents the scientific rationale for determination of the hazard potential of a chemical and the subsequent assignment of SKs. A case study of acrylamide is presented as an application of the NIOSH strategy.     

Determination of free and total bisphenol A in human urine to assess daily uptake as a basis for a valid risk assessment

Bisphenol A (BPA) is widely distributed and exhibits weak estrogenic activity. In contrast to BPA, the corresponding glucuronide metabolite is not estrogenic. Therefore, free and total BPA were determined in human urine samples to assess the significance of free BPA for risk assessment. In only 10% of 474 samples from 287 subjects was free BPA detected in a range from 相似文献   

Potency values from the local lymph node assay: Application to classification,labelling and risk assessment

Hundreds of chemicals are contact allergens but there remains a need to identify and characterise accurately skin sensitising hazards. The purpose of this review was fourfold. First, when using the local lymph node assay (LLNA), consider whether an exposure concentration (EC3 value) lower than 100% can be defined and used as a threshold criterion for classification and labelling. Second, is there any reason to revise the recommendation of a previous ECETOC Task Force regarding specific EC3 values used for sub-categorisation of substances based upon potency? Third, what recommendations can be made regarding classification and labelling of preparations under GHS? Finally, consider how to integrate LLNA data into risk assessment and provide a rationale for using concentration responses and corresponding no-effect concentrations. Although skin sensitising chemicals having high EC3 values may represent only relatively low risks to humans, it is not possible currently to define an EC3 value below 100% that would serve as an appropriate threshold for classification and labelling. The conclusion drawn from reviewing the use of distinct categories for characterising contact allergens was that the most appropriate, science-based classification of contact allergens according to potency is one in which four sub-categories are identified: ‘extreme’, ‘strong’, ‘moderate’ and ‘weak’. Since draining lymph node cell proliferation is related causally and quantitatively to potency, LLNA EC3 values are recommended for determination of a no expected sensitisation induction level that represents the first step in quantitative risk assessment.     

Resources for global risk assessment: the International Toxicity Estimates for Risk (ITER) and Risk Information Exchange (RiskIE) databases

The rate of chemical synthesis and use has outpaced the development of risk values and the resolution of risk assessment methodology questions. In addition, available risk values derived by different organizations may vary due to scientific judgments, mission of the organization, or use of more recently published data. Further, each organization derives values for a unique chemical list so it can be challenging to locate data on a given chemical. Two Internet resources are available to address these issues. First, the International Toxicity Estimates for Risk (ITER) database (www.tera.org/iter) provides chronic human health risk assessment data from a variety of organizations worldwide in a side-by-side format, explains differences in risk values derived by different organizations, and links directly to each organization's website for more detailed information. It is also the only database that includes risk information from independent parties whose risk values have undergone independent peer review. Second, the Risk Information Exchange (RiskIE) is a database of in progress chemical risk assessment work, and includes non-chemical information related to human health risk assessment, such as training modules, white papers and risk documents. RiskIE is available at http://www.allianceforrisk.org/RiskIE.htm, and will join ITER on National Library of Medicine's TOXNET (http://toxnet.nlm.nih.gov/). Together, ITER and RiskIE provide risk assessors essential tools for easily identifying and comparing available risk data, for sharing in progress assessments, and for enhancing interaction among risk assessment groups to decrease duplication of effort and to harmonize risk assessment procedures across organizations.     

Evaluation of community pharmacists' preparedness for the provision of cardiovascular disease risk assessment and management services: A study with simulated patients

Background

Individuals who suffer from major cardiovascular events every year have one or more risk factors. Cardiovascular disease (CVD) risk assessment is an important strategy for the early identification of modifiable risk factors and their management. There is substantial evidence that shifting the focus from treatment to primary prevention reduces the burden of CVD.

CYP2E1 expression in bone marrow and its intra- and interspecies variability: approaches for a more reliable extrapolation from one species to another in the risk assessment of chemicals

When characterizing the health risks for man by exposure to chemicals, species-specific differences have to be taken into consideration, otherwise extrapolation from animal data to the human situation would be inadequate. The site-specific toxicity of chemicals may be explained by the following alternatives: (1) reactive metabolites are generated in the liver and subsequently transported to the target tissue(s); (2) metabolism of the parent compound occurs in the target tissue, a pathway by which the enzymes necessary for activation must be expressed in the target tissue. Cytochrome P450 2E1 (CYP2E1) is an important phase-I enzyme activating several chemicals. In the study described in this paper, myeloid intra- and interspecies variability in the expression of CYP2E1 has been investigated in rats, rabbits and man, because the bone marrow represents an important target organ for toxic effects of several chemicals, e.g. benzene. CYP2E1 at the protein level was detected by Western blotting and enzyme activities were determined by CYP2E1-dependent hydroxylation of chlorzoxazone (CLX). In the bone marrow of Wistar rats, the CLX hydroxylase activities were within the same order of magnitude (range: 0.1–0.4 pmol/mg protein per min) as previously described for mice (range 0.2–0.8 pmol/mg protein per min), whereas the CYP2E1 activities in two strains of rabbits were significantly higher (range: 1.7–4.7 pmol/mg protein per min) than in the rodents (P < 0.05). In human CD34⁺ bone marrow stem cells, CYP2E1 could also be detected on the protein level by Western blotting. The data demonstrate a presence of CYP2E1 in the bone marrow of all species investigated, thus supporting the hypothesis of CYP2E1-dependent local metabolism of several chemicals as a factor possibly contributing to their myelotoxicity and haematotoxicity. The data show that intraspecies/intrastrain variability of CYP2E1 activity in rodents is small. However, CYP2E1 activity between rodents and a non-rodent species was quite different indicating considerable interspecies variability. Received: 5 August 1999 / Accepted: 5 November 1999